Phosphodiesterase 5 (PDE5) Is Highly Expressed in Cancer-Associated Fibroblasts and Enhances Breast Tumor Progression.

Catalano Catalano,Giordano Giordano,Gelsomino Gelsomino,Augimeri Augimeri,Panza Panza,Győrffy Győrffy,Malivindi Malivindi,Marsico Marsico,Barone Barone,Bonofiglio Bonofiglio,Andò Andò

doi:10.3390/cancers11111740

Catalano Catalano, Giordano Giordano + Show 9 more

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https://doi.org/10.3390/cancers11111740

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Abstract

The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was correlated to a shorter overall survival. Treatment of CAFs, isolated from breast tumor biopsies, with selective PDE5 inhibitors inhibited their proliferation, motility, and invasiveness, and negatively controlled tumor–stroma interactions in both ‘in vitro’ and ‘in vivo’ models. PDE5 stable overexpression transformed immortalized mouse embryonic fibroblasts (MEFs) towards an activated fibroblast phenotype, impacting their intrinsic characteristics and paracrine effects on breast cancer cell growth and migration through an enhanced production of the C-X-C motif chemokine 16 (CXCL16). On the other hand, CAF exposure to PDE5 inhibitors was associated with reduced CXCL16 expression and secretion. Importantly, CXCL16 levels in breast cancer stroma showed a strong correlation with PDE5 levels and poor patient outcomes. In conclusion, PDE5 is overexpressed in breast cancer stroma, enhances the tumor-stimulatory activities of fibroblasts, and impacts clinical outcomes; thus, we propose this enzyme as an attractive candidate for prognosis and a potential target for treatments in breast cancer patients.

Highlights

Breast cancer is the most commonly diagnosed neoplasia among women worldwide, accounting for 25% of all cancer cases [1]
In order to further examine the role of CXCL16 as a key player in PDE5-associated stromal activation, we evaluated changes in CXCL16 expression in human breast cancer-associated fibroblasts (CAFs) treated with PDE5 inhibitors
While the initial view was that PDE5 is highly expressed and can function in breast cancer cells, we show here that this enzyme is upregulated in CAFs when compared to normal fibroblasts and this overexpression is a part of the dialogue between breast cancer cells and CAFs, allowing CAFs via

Summary

Introduction

Breast cancer is the most commonly diagnosed neoplasia among women worldwide, accounting for 25% of all cancer cases [1]. Malignant initiation and progression is associated with the activation of stromal fibroblasts into myofibroblasts or carcinoma-associated fibroblasts (CAFs), characterized by the expression of α-smooth muscle actin (α-SMA) and fibroblast activated protein (FAP) [2]. CAFs are the predominant cellular component within the host stromal constituents and, acting as a motile cohesive unit able to penetrate the cancerous compartment and as a paracrine signaling source niche, possess the abilities to drive tumor cell proliferation, survival, migration and invasion. The key features of CAFs, which distinguish them from their normal counterparts, include their growth characteristic, migratory behavior, and biosynthetic activities, such as altered expression of growth factors and cytokines (e.g., transforming growth factor β (TGFβ), insulin-like growth factor I (IGF-I) and II (IGF-II), leptin, interleukin-6 (IL-6), chemokine (C-C motif) ligand 7 (CCL7), C-X-C motif Chemokine 12 (CXCL12) and

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